1. Field of the Invention
The present invention relates most substantially to the field of in vivo imaging. The invention provides methods and compositions for use in improved light-based imaging and treatment modalities based upon the use of low-scattering, oxygen-carrying blood substitutes. The use of hemoglobin solutions in combination with OCT imaging is a particular example within the invention. The compositions, methods and uses of the invention have important advantages in imaging tissues that are intolerant of ischemia.
2. Description of Related Art
Non-invasive diagnostic imaging is now widely used in clinical practice. One of the commonly employed techniques is imaging with ultrasound, which measures the intensity of backscattered sound waves. However, ultrasound technology is limited both in the rate at which images can be generated and in the structural detail that can be provided. Thus, ultrasound is not best suited to in vivo imaging on a precise scale or in connection with rapidly moving biological tissues. Such drawbacks reduce the applications of ultrasound, e.g., limiting its use in cardiovascular imaging.
A promising new technique, optical coherence tomography (OCT), has been developed and proposed for use in certain aspects of in vivo imaging. OCT is analogous to ultrasound, but measures the intensity of backscattered light rather than sound waves. Since light travels faster than sound and has a substantially shorter wavelength, the use of OCT provides micron scale resolution (Huang et al., 1991) and faster-than-video imaging speeds (Rollins et al., 1998). The relative simplicity of the instrumentation also allows for inexpensive construction.
Early biomedical applications of OCT focused on imaging stationary and transparent tissues, such as the eye, where imaging depths can be deeper than 2 cm (Hee et al., 1995). Further developments have been applied to non-transparent tissues, such as skin, where structures as deep as 1-2 mm have been visualized (Schmitt et al., 1995). Dynamic, but nearly transparent, structures such as the developing in vivo tadpole heart, have also been studied using OCT (Boppart et al., 1997).
OCT has now been proposed for use in imaging other biological tissues, and there has recently been increasing interest in applying OCT to the cardiovascular system. In vivo intravascular imaging has been reported in rabbit aorta (Fujimoto et al., 1999), and in vitro studies with coronary arteries have suggested a method of determining fibrous cap thickness of atherosclerotic plaques (Brezinksi et al., 1996; Patwari et al., 2000). However, despite such proposals, the use of OCT has yet to prove satisfactory in many biological imaging applications.
The limitations of applying OCT to dynamic, non-transparent biological structures are particularly evident in attempts at cardiovascular imaging. Although optical Doppler tomography (ODT), which combines Doppler velocimetry with OCT, has been used to assess blood flow in the chick chorioallantoic membrane and in rodent skin, problems with signal attenuation were noted (Chen et al., 1997). Other reports have also indicated that potential in vivo applications of OCT imaging are complicated by the presence of blood in the imaging field, which results in substantial signal attenuation (Brezinski et al., 2001). Therefore, although cardiovascular imaging with light seemed to offer a solution to the drawbacks of ultrasound, practical applications have proven problematical due to significant optical attenuation.
In preliminary attempts at OCT intravascular imaging in the rabbit aorta, saline infusions were required to obtain adequately defined images (Fujimoto et al., 1999). Others have commented that the use of such saline flushes will likely need to be eliminated in order for intravascular OCT imaging to advance (Brezinski et al., 2001). The alternative approach proposed was to modify plasma to match the index of refraction to that of red blood cells, i.e., increasing the serum refractive index closer to that of the erythrocyte cytoplasm (Brezinski et al., 2001). However, whilst such “index matching” techniques have been pursued in relatively crude in vitro experiments using dextran and intravenous contrast agents, the in vitro tests have been less than convincing and the proposal has not been validated in acceptable in vivo models.
Therefore, despite attempts to refine or optimize existing imaging technology, there remains in the art a need for improved in vivo imaging techniques, particularly rapid techniques that provide high resolution. The development of improved techniques that can be effectively applied to imaging in the cardiovascular system, heart, brain and other blood-rich tissues is particularly desirable. In trying to expand the use of in vivo OCT imaging into such important fields, it would be important to overcome the existing need for saline flushes, which currently limits OCT applications in such areas. Accordingly, the ability to rapidly provide high resolution images of blood-rich tissues without causing ischemic tissue damage would represent a particularly significant advance.